Topical preparation containing a suspension of solid lipid particles

ABSTRACT

An aqueous suspension of solid lipoid nanoparticles, comprising at least one lipid and preferably also at least one emulsifier, for topical application to the body, is provided. The solid lipoid nanoparticles have a mean particle size of between 50-1000 nm and their concentration is between 0.01-60 wt %, by weight of the suspension. Also topical preparations, comprising said suspension of solid lipoid nanoparticles, are provided. A medicament can be incorporated into the continuous phase of the suspension or in a vehicle, which is added to said suspension.

PRIOR APPLICATION

This application is a continuation of application Ser. No. 08/131,480,filed Oct. 4,1993 now abandoned, which is a continuation of U.S. patentapplication Ser. No. 07/857,467 filed Mar. 25, 1992, now abandoned.

The present invention is concerned with a suspension of solid lipidparticles and with liquid or semisolid preparations, containing saidsuspension, for topical application to the body, and with themanufacture thereof.

BACKGROUND OF THE INVENTION

There is a great variety of known liquid or semisolid preparations fortopical application to the body, and they are generally based on aqueousor other polar liquids, on liquid or semisolid lipids, or on mixturesthereof. When the preparation is based on a mixture of an aqueous liquidand a lipid substance, the preparation is an emulsion, which may be awater-in-oil (w/o) emulsion in which the lipid substance is thecontinuous phase, or an oil-in water (o/w) emulsion in which the aqueousliquid is the continuous phase. Each of these types of emulsions isprepared with its own type of emulsifier. EP-B-69423 shows that the typeof emulsion is determined by the type of emulsifier used, rather than bythe relative concentrations of aqueous or lipid components present.Examples of known emulsions of the w/o type are the ointments, whichgenerally are semisolid. As examples of known emulsions of the o/w typelotions, which are liquid, and creams and gels, which are semisolid, canbe mentioned.

The liquid or semisolid lipids, contained in the above-described liquidor semisolid w/o or o/w emulsions, generally are responsible for acosmetically and medically important effect, viz. occlusion. Byocclusion is meant the formation of a "barrier", which causes reductionof water loss through the epidermis, after treatment thereof with suchlipid containing emulsions. The occlusive effect is positivelycorrelated to the lipid content of the emulsion. The resulting desirablecosmetic effect of occlusion is emolliency. The resulting desirablemedical effect of occlusion is a better penetration into the skin and abetter effectiveness of many medicaments, incorporated into an occludingemulsion, after topical application of the same. On the other hand, suchlipid containing emulsions have the disadvantage that they are greasyand messy, resulting in a shining appearance of the treated area and instaining of the clothes, and these undesirable properties are alsopositively correlated to the lipid content of the emulsion.

H. Tsutsumi et al., J. Soc. Cosmet. Chem., 30, 1979, 345-356 describedoil-in-water emulsions of different particle size distribution preparedout of water, solid paraffin (melting point 48° C.) and a mixture ofpolyoxyethylene (20) sorbitan monooleate and sorbitan monooleate. Thesolid particles of the resulting emulsions had a mean diameter of about3-65 μm. The occlusivity of the emulsions was found to be inverselyproportional to the particle size. However, in the present inventors'experience these types of emulsions, containing solid paraffin particlesof micrometer dimensions (microparticles), were found to be inherentlyunstable. Also, these types of emulsions were found to exert a lowerocclusivity as compared with conventional emulsions.

EP-B-167825 discloses a medicament-containing carrier system for peroraluse, comprising a 1-20 wt % aqueous suspension of solid lipoidnanopellets with a particle size of 50-1000 nm, the lipoid particlescontaining 5-70 wt % of lipids, 0.01-70 wt % of an emulsifier and0.05-25 wt % of the medicament. Due to their small size, the lipoidparticles in toto are easily absorbed from the gastro-intestinal tract.Among the advantages of this type of drug-containing carrier system fororal administration an improved bioavailability of those medicaments,which are poorly soluble, poorly absorbed from the digestive tract,chemically or enzymatically inactivated in the digestive tract or proneto the so-called first-pass effect, is to be mentioned in particular.

SUMMARY OF THE INVENTION

The present invention provides, for topical application to the body, astable aqueous suspension of solid lipoid nanoparticles, comprising atleast one lipid and preferably also at least one emulsifier.

Also is provided, for topical application to the body, a preparationwhich comprises a stable aqueous suspension of solid lipoidnanoparticles, comprising at least one lipid and preferably also atleast one emulsifier, and having a mean particle size of between 50 and1000 nm, and optionally comprising one or more medicaments outside thesolid lipoid nanoparticles.

The invention further provides manufacturing methods for said suspensionand preparation, comprising the steps of:

a. melting an appropriate quantity of a solid lipid or a mixture of(solid) lipids in a heated aqueous liquid, preferably in the presence ofan effective amount of emulsifier(s);

b. vigorously dispersing the molten lipid(s) in the aqueous liquid, in amanner resulting in the formation of molten lipoid droplets of 50-1000nm;

c. allowing the dispersion to cool until the dispersed lipoid dropletssolidify and a suspension of solid lipoid nanoparticles is formed;

d. optionally adding to the suspension, obtained in step c., apharmaceutically acceptable vehicle; and

e. optionally adding to the continuous phase of the suspension or to thepharmaceutically acceptable vehicle a topically effective amount of oneor more medicaments.

LEGENDS TO THE FIGURES

FIG. 1 is a graphical representation of the blanching of the skin as afunction of time, after topical application of fourhydrocortisone-17α-butyrate containing preparations.

FIG. 2 is a graphical representation of the mean oxiconazoleconcentrations as a function of the penetration depth into pig's nail,after topical application of two oxiconazole nitrate containingpreparations.

FIG. 3 is a graphical representation of the total amounts ofoxiconazole, penetrated into pig's nail, after topical application oftwo oxiconazole nitrate containing preparations.

DETAILED DESCRIPTION OF THE INVENTION

It has now been found that by partially or completely replacing theliquid or semisolid lipid containing emulsion, as generally used in theart, by a suspension of solid lipoid particles having a mean particlesize of between 50-1000 nm (nanoparticles), a very stable preparation ismade which has maintained the occlusive effect, generally known to beinherent to lipid containing emulsions, while the appreciation withrespect to the cosmetic properties of the preparations according to thepresent invention is greatly improved as compared to that of the lipidcontaining emulsions known in the art. The novel preparation can beadvantageously used for providing emolliency and softness to the skin.

It has further been found that topically effective medicaments can beadvantageously incorporated into the continuous phase of the novelsuspension of solid lipoid nanoparticles. In addition to knownadvantages, which are inherent to drug-containing occludingpreparations, among which a better penetration into the skin and nailsand a better effectiveness of the medicaments incorporated therein areto be mentioned, said novel preparations have also shown othersurprising effects: a better regulated drug delivery, especially asustained release, and a lower irritancy of intrinsically irritantmedicaments, incorporated therein.

The invention therefore provides for topical application to the body anaqueous suspension of solid lipoid nanoparticles, comprising at leastone lipid and preferably also at least one emulsifying agent.

The invention also provides, for topical application to the body,preparations, comprising said aqueous suspension of solid lipoidnanoparticles.

It will be appreciated that topical application to the body includes theapplication to the skin, hairs and nails.

The solid lipoid nanoparticles according to the invention have a meanparticle size between 50-1000 nm. Preferably, the particle size isbetween 100-400 nm, more preferably between 150-300 nm.

The concentration of the solid lipoid nanoparticles according to theinvention is between 0.01-60%, preferably 5-45%, more preferably 10-30%,by weight based on the weight of the suspension.

The lipoid nanoparticles according to the present invention are solid atroom temperature. Therefore, the solid lipids of the nanoparticlesaccording to the invention are those lipids having a melting temperaturerange between 30-100° C., preferably between 40-95° C. When mixtures oflipids are employed, they may partly contain lipids having a meltingtemperature range lower or higher than between 30 and 100° C.,respectively, as long as the complete mixture has a melting temperaturerange which is within these limits.

The lipoid nanoparticles of the present invention can comprise a singlesolid lipid or a mixture of (solid) lipids. Suitable solid lipids arefor example:

higher saturated alcohols, in particular the aliphatic alcohols having14-30 carbon atoms, such as cetostearyl alcohol;

waxes, such as carnauba wax;

hydrocarbons, such as solid paraffins (=hard paraffins);

sphingolipids;

synthetic esters, such as cetyl palmitate;

higher fatty acids of 12-30 carbon atoms, such as stearic acid;

and the mono-, di- and triglycerides of higher saturated fatty acidshaving 10-30 carbon atoms, such as glyceryl trilaurate and hydrogenatedcastor oil.

A preferred solid lipid according to the invention is solid paraffin,having a melting temperature range of 54-57° C.

Although there exist solid lipids with which a preparation according tothe invention can be made without any emulsifier being added (examplesof these are the sphingolipids), in most cases an emulsifier is needed.

It will be appreciated that the nanoparticles, formed from a mixture oflipids and emulsifying agents, still have to be solid at roomtemperature.

The concentration of emulsifier(s) will vary with the type of the lipidsand emulsifiers used and may be from 0.01-20%, preferably 0.1-10%, morepreferably 1-5%, by weight based on the weight of the suspension.

A variety of emulsifiers, belonging to both the groups of w/o and o/wemulsifiers and ranging in HLB (Hydrophilic-Lipophilic Balance) numberfrom about 2 to about 80, has been found to be effective for dispersingthe molten solid lipid(s) in the heated aqueous liquid. Preferably, theemulsifier has a HLB number of about 8-40. The choice of the emulsifierwill depend of the particular solid lipid(s) used.

Examples of suitable emulsifiers are:

the cationic emulsifiers, such as cetyltriethylammonium bromide;

the anionic emulsifiers, such as sodium lauryl sulphate;

the amphoteric emulsifiers, such as hydroxyethyl imidazoline (VARINE®);

block copolymers, such as polyoxyethylenepolyoxypropylene alkyl ethers(e.g. PLURONIC F68®);

non-ionic emulsifiers, such as polyoxyethylene sorbitan fatty acidesters (e.g. TWEEN 20®), polyoxyethylene alkyl ethers (e.g. BRIJ 97® andCETOMACROGOL 1000®), polyoxyethylene fatty acid esters (e.g. MYRJ 52®),sorbitan esters (e.g. SPAN 80®), sucrose esters (e.g. WASAG ESTER 7®);

and further suitable emulsifiers, such as the lecithins, the siliconesurfactants, the retains and the polyglycerol fatty acid esters.

Preferably, non-ionic emulsifiers are used. More preferably, theemulsifiers are chosen from the groups of polyoxyethylene alkyl ethersand sorbitan esters.

A mixture of different emulsifiers can also be used advantageously.

The continuous phase of the suspension of solid lipoid nanoparticlesaccording to the present invention preferably comprises water, but mayalso comprise a mixture of water with non-aqueous, polar liquids, forexample alcohols, such as ethyl alcohol, glycerol, propylene glycol, andpyrrolidones, such as N-methyl pyrrolidone and 2-pyrrolidone.

The invention further provides a method for the production of an aqueoussuspension of solid lipoid nanoparticles for topical application to thebody, comprising the steps of:

a. melting an appropriate quantity of at least one solid lipid (0.01-60%by weight based on the weight of the suspension), and preferably also aneffective amount of at least one emulsifier (0.01-20% by weight based onthe weight of the suspension) in a heated aqueous liquid, preferablywater;

b. vigorously dispersing the molten lipid(s) in the aqueous liquid, in amanner resulting in the formation of molten lipoid droplets having aparticle size of between 50 and 1000 nm;

c. allowing the dispersion to cool until the dispersed lipoid dropletssolidify and a suspension of solid lipoid nanoparticles is formed.

The vigorous dispersing of the molten lipid(s) in the aqueous liquid isessential for the formation of minute droplets of the molten lipid(s).This may be achieved by any of various methods known in the art, such asthe method described in EP-B-167825, which comprises mechanical mixingwith a high-speed mixer, optionally followed by ultrasound-treatment. Amethod, which comprises the use of a high sheer homogenizer valvemachine, such as a Manton-Gaulin homogenizer, can also be used. Apreferred method is microfluidization. A MICROFLUIDIZER® device,manufactured by Microfluidics Corporation, Newton, Mass., USA, can beadvantageously used to achieve any desired droplet micronization withinthe range of 50-1000 nm. The size of the droplets is further influencedby diverse factors, such as the lipoid material used, the emulsifier(s),the temperature and pressure during treatment and the duration oftreatment.

After the minute droplets have been formed as described above, thedispersion is allowed to cool until the lipoid droplets solidify,thereby forming the solid lipoid nanoparticles according to theinvention. The cooling can be done actively, according to methods knownin the art.

The suspension of solid lipoid nanoparticles in an aqueous liquid thusproduced, can be used as such on the skin and it has the above-describedattractive cosmetic properties. It can also be used to accommodate atopically effective medicament, with the resulting additional, medicallyattractive properties as described above. Alternatively, thissuspension, with or without the presence of a topically effectivemedicament, can be further mixed with an appropriate, preferablyaqueous, polar liquid, with a liquid or semisolid lipid, or with amixture thereof which may in its turn be a w/o emulsion such as anointment, or an o/w emulsion such as a lotion, a cream or a gel. Thecomplete preparation, to be applied to the body, may also containfurther pharmaceutical excipients.

Topically effective medicaments which may be used in or with thesuspension of solid lipoid nanoparticles according to the invention arefor example antibiotics, chemotherapeutic agents, anti-viral agents,non-steroidal anti-inflammatory compounds such as indomethacin,salicylic acid and derivatives thereof, anti-pruritics, tar products,nicotinic acid and derivatives thereof, retinoids, sebum synthesisinhibitors such as the imidazole-ethanol esters of EP-B-124186,wound-healing agents, growth factors, or disinfectants such ashexachlorophene, but preferably anti-mycotics such as oxiconazolenitrate, steroidal anti-inflammatory compounds such as hydrocortisone,hydrocortisone-17α-butyrate, budesonide or triamcinolone acetonide,anti-proliferatives, anti-psoriatics, anti-eczema agents and dithranolare added to the preparations according to the present invention. Acombination of two or more topically effective medicaments can also beused.

Non-aqueous, polar liquids, which may be mixed with the suspension ofsolid lipoid nanoparticles according to the invention, are for examplealcohols such as ethyl alcohol, glycerol, propylene glycol, andpyrrolidones such as N-methyl pyrrolidone and 2-pyrrolidone.

Liquid or semisolid lipids which may be mixed, as such or in a w/o oro/w emulsion, with the suspension of solid lipoid nanoparticlesaccording to the invention are for example:

waxes, such as jojoba oil;

mineral oils, such as liquid or soft paraffins;

fatty alcohols, such as oleyl alcohol;

esters, such as isopropyl myristate;

vegetable oils, such as coconut oil;

fatty acids, such as linoleic acid; and

silicone oils.

When a w/o or an o/w emulsion is used, to be mixed with the suspensionof solid lipoid nanoparticles according to the invention, it will alsocontain an appropriate w/o or o/w emulsifier, as known in the art ofmaking such w/o or o/w emulsions.

Pharmaceutical excipients which are commonly used are buffers,preservatives, anti-oxidants, moisturizers, penetration enhancers, UVabsorbers, dyes, and fragrances.

The invention also further provides a method of production for thepreparations, comprising the aqueous suspension of solid lipoidnanoparticles, for topical application to the body, which comprises theadditional step of:

adding to the suspension of solid lipoid nanoparticles an appropriate,preferably aqueous, polar liquid, a gel based on such a liquid, a liquidor semisolid lipid, an o/w emulsion, or a mixture of any of the above,to make a solution, a gel, a w/o emulsion or an o/w emulsion in whichthe solid lipoid nanoparticles are suspended.

The invention also still further provides a method of production for thepreparation, comprising an aqueous suspension of solid lipoidnanoparticles and one or more medicaments outside said nanoparticles,which comprises the additional step of:

adding to the continuous phase of the suspension of solid lipoidnanoparticles, or to the solution, w/o emulsion or o/w emulsion in whichthe solid lipoid nanoparticles are suspended, a topically effectiveamount of a medicament and optionally pharmaceutically acceptableexcipients.

All publications and patent applications cited in this specification areherein incorporated by reference as if each publication or patentapplication were specifically and individually indicated to beincorporated by reference.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity andunderstanding, it will be readily apparent to those of ordinary skill inthe art in light of the teachings of this invention that certain changesand modifications may be made thereto without departing from the spiritand scope of the appended claims.

The following Examples will illustrate the invention. Of thecompositions described therein, all percentages quoted are by weight.

EXAMPLE 1 Production of Suspensions of Solid Lipoid Particles

1.1. A suspension of solid lipoid microparticles was produced asfollows:

300 g of solid paraffin, melting point range 54-57° C., was heated at80° C. 50 g of CETOMACROGOL 1000® (HLB=16.1) was dissolved in 650 ml ofwater at 80° C. The lipid phase was added to the aqueous phase and thedispersion homogenized during 5 minutes with a TURRAX® homogenizer, at2000 R.P.M., and cooled to ambient temperature. The resulting suspensionof solid lipoid microparticles had a particle size of more than 2 μm(measured by light microscopy). It was not stable, separation occurringwithin 20 hours of standing.

1.2. A suspension of solid lipoid nanoparticles was produced as follows:

300 g of solid paraffin, melting point range 54-57° C., was heated at80° C. 50 g of CETOMACROGOL 1000® was dissolved in 650 ml of water at80° C. The lipid phase was added to the aqueous phase and the dispersionhomogenized during 5 minutes with a TURRAX® homogenizer, at 2000 R.P.M.This dispersion was fed to a MICROFLUIDIZER® device (type M-110 Tequipped with an interaction chamber F₂₀ Y and a back pressure chamberH₃₀ Z), heated in a water bath at 70° C. and operating at a pressure of10,000 PSI.

After a single run through the MICROFLUIDIZER® device, the emergingdispersion was cooled to ambient temperature. The resulting suspensionof solid lipoid nanoparticles had a mean particle size (measured bydynamic light scattering) of 132 nm, and was very stable: even after 30months of storage there occurred no separation and no agglomeration ofparticles.

1.3. Another suspension of solid lipoid nanoparticles was produced inthe same way as 1.2., using:

100 g of lauric acid triglyceride (DYNASAN-112®), melting point range43-45° C., and 40 g of sodium lauryl sulphate (HLB=40), dissolved in 860ml of water at 55° C.

After a single run through the MICROFLUIDIZER® device, heated in a waterbath at 50° C., the emerging dispersion was cooled to ambienttemperature, resulting in a very stable suspension of solid lipoidnanoparticles, having a mean size of 180 nm.

1.4. Yet another suspension of solid lipoid nanoparticles was producedin the same way as 1.2., using:

50 g of glycerylstearate, melting point 56° C., and 950 ml of water at80° C.

After two runs through the MICROFLUIDIZER® device, heated in a waterbath at 70° C., the emerging dispersion was cooled to ambienttemperature, resulting in a stable suspension of solid lipoidnanoparticles, having a mean size of 191 nm.

1.5. Yet another suspenion of solid lipoid nanoparticles was produced inthe same way as 1.2., using:

50 g of solid paraffin, melting point range 54-57° C., with 10 g of SPAN85® (HLB=1.8), dissolved in the molten paraffin, and 940 ml of water at80° C.

After three runs through the MICROFLUIDIZER® device, heated in a waterbath at 70° C., the emerging dispersion was cooled to ambienttemperature, resulting in a stable suspension of solid lipoidnanoparticles, having a mean size of 118 nm.

1.6. Yet another suspension of solid lipoid nanoparticles was producedin the same way as 1.2., from:

50 g of solid paraffin, melting point range 54-57° C., with 5 g ofPHOSPHOLIPON 90® (a lecithin mixture with min. 90% hydrogenated sojaphosphatidylcholine and max. 6% Lysophosphatidylcholine, HLB±80, sold byNattermann Phospholipid GmbH), dissolved in the molten paraffin, and 945g of water at 80° C.

After two runs through the MICROFLUIDIZER® device, heated in a waterbath at 70° C., the emerging dispersion was cooled to ambienttemperature, resulting in a stable suspension of solid lipoidnanoparticles, having a mean size of 428 nm.

1.7. Yet another suspension of solid lipoid nanoparticles was producedin the same way as 1.2., from:

200 g of solid paraffin, melting point range 54-57° C., and 200 g ofTAGAT 02® (polyoxyethylene-glyceryl-monooleate), dissolved in 600 g ofwater.

After a single run through the MICROFLUIDIZER® device, heated in a waterbath at 80° C., the emerging dispersion was cooled to ambienttemperature, resulting in a very stable suspension of nanoparticles,having a mean size of 140 nm.

EXAMPLE 2 Production of a Conventional Cream, and of Creams Containing aSuspension of Solid Lipoid Microparticles or a Suspension of SolidLipoid Nanoparticles

2.1. A conventional cream was produced as follows:

52 g of petrolatum, 72 g of cetostearyl alcohol, 88.8 g of propyleneglycol and 0.8 g of methyl-p-hydroxybenzoate (NIPAGIN M®) were heatedtogether at 70° C. 16 g of CETOMACROGOL 1000® were dissolved in 176 g ofwater at 70° C. Both phases were mixed together, concurrently using astirrer at 200 R.P.M. and a TURRAX® homogenizer at 2000 R.P.M. Thedispersion was cooled under reduced pressure to ambient temperature.

2.2. Another conventional cream was produced in the same way as 2.1.,from:

26 g of cetostearyl alcohol heated to 70° C. and 4 g of CETOMACROGOL1000® dissolved in 50 g of water at 70° C. Both phases were mixedtogether, concurrently using a stirrer at 200 R.P.M. and a TURRAX®homogenizer at 2000 R.P.M. The dispersion was cooled to ambienttemperature under reduced pressure.

2.3. A cream containing a suspension of solid lipoid microparticles wasproduced as follows:

200 g of the suspension according to 1.1. were mixed at 30° C. with 80 gof the cream according to 2.2., using in succession a mixer at 200R.P.M. and a TURRAX® homogenizer at 2000 R.P.M. The resulting cream hada granular appearance.

2.4. A cream containing a suspension of solid lipoid nanoparticles wasproduced in the same way as in 2.3., by mixing 200 g of the suspensionaccording to 1.2., with 80 g of the cream according to 2.2.

2.5. Another cream containing a suspension of solid lipoid nanoparticleswas produced in the same way as in 2.3., by mixing 200 g of thesuspension according to 1.2., to which 2 g of NIPAGIN M® was added, with200 g of the cream according to 2.1.

2.6. Yet another cream containing a suspension of solid lipoidnanoparticles was produced by mixing 134 g of the suspension accordingto 1.2., to which 2 g of NIPAGIN M® were added, at 30° C. with 22 g ofBRIJ 99®, 22 g of cetyl alcohol and 22 g of propylene glycol, with astirrer at 200 R.P.M.

EXAMPLE 3 Production of a Conventional Gel, and a Gel Containing aSuspension of Solid Lipoid Nanoparticles

3.1. A conventional gel was produced by suspending 20 g of CARBOPOL 940®in 980 g of water, adjusted to pH=5.0 with TRIS (tromethamine).

3.2. A gel containing a suspension of solid lipoid nanoparticles wasproduced by mixing (with a propeller stirrer at 1500 R.P.M.) during 10minutes 600 g of the suspension according to 1.3. with 400 g of the gelaccording to 3.1.

3.3. Yet another suspension of solid lipoid nanoparticles was producedin the same way as 1.2., from:

100 g of hydrogenated castor oil (CUTINA HR®), melting point about 85°C., and 40 g of sodium lauryl sulphate, dissolved in 860 ml of water at85° C.

After a single run through the MICROFLUIDIZER® device, heated in a waterbath at 90° C., the emerging dispersion was cooled to ambienttemperature, resulting in a stable suspension of solid lipoidnanoparticles having a mean size of 195 nm. After 24 hours of storagethis suspension gelated, the gel having good cosmetic properties.

EXAMPLE 4 Production of a Lotion, Containing a Suspension of SolidLipoid Nanoparticles and a Lotion Containing Solid Lipoid Nanoparticlesand a Medicament

4.1. A lotion containing a suspension of solid lipoid nanoparticles wasproduced as follows:

A clear liquid mixture containing 15 g of isopropylstearate and 15 g ofoctamethylcyclotetrasiloxane was added to a clear solution containing119 g of water, 3 g of polyoxyethylene (20) oleylether and 50 g ofpropylene glycol at 75° C.

At this temperature the mixture was stirred at 200 R.P.M. and wasconcurrently homogenized using a TURRAX® homogenizer at 2000 R.P.M. Theresulting liquid emulsion was cooled to 30° C whilst the mixture wasstirred at 100 R.P.M.

100 g of the suspension according to 1.2. was added to the liquidemulsion at 30° C. and mixed using a stirrer at 100 R.P.M.

A thin liquid lotion containing liquid emulsion droplets and solidlipoid nanoparticles was obtained. The lotion had good cosmeticproperties.

4.2. A lotion containing solid lipoid nanoparticles and a medicament wasproduced as follows:

To the dispersion of 1.2., 5 g of NIPAGIN B® and 10 g of NIPAGIN A® wereadded. 33.3 g of this preserved dispersion were mixed with 48.35 g of aclear 2.1 wt/vol % aqueous dispersion of hydroxypropylcellulose using astirrer at 200 R.P.M. 2 g of benzyl alcohol, 0.2 g of a lime fragrance,15 g of N-acetylcysteine and 1.15 g of oxiconazole nitrate were added tothe mixture and mixed at 150 R.P.M. at ambient temperature.

EXAMPLE 5 Production of an Ointment, Containing a Suspension of SolidLipoid Nanoparticles

5.1. An ointment containing a suspension of solid lipoid nanoparticleswas produced as follows:

At 30° C. 25 g of isopropylstearate, 54 g ofoctamethylcyclotetrasiloxane and 6 g of cetyl dimethicone copolymer weremixed using a stirrer at 300 R.P.M. A clear liquid oily mixture wasobtained.

100 g of the suspension according to 1.2. was diluted with an aqueoussolution of sodium chloride (1 wt %) to 215 g.

The aqueous suspension of solid lipoid nanoparticles was added to theoily mixture at 30° C., whilst the mixture was concurrently stirred at200 R.P.M. using a stirrer. The resulting mixture was homogenized usinga TURRAX® homogenizer at 2000 R.P.M., whilst the product wasconcurrently stirred at 100 R.P.M.

In this way an ointment containing solid lipoid nanoparticles and havingvery good cosmetic properties was obtained.

EXAMPLE 6 Production of Creams and Ointments, Containing a Suspension ofSolid Lipoid Nanoparticles and a Medicament

6.1. 5 mg of dithranol was hand-mixed in a mortar with 5 g of the creamaccording to 2.5.

6.2. 10 mg of tretinoin was hand-mixed in a mortar with 10 g of thecream according to 2.5.

6.3. 10 mg of dithranol was hand-mixed in a mortar with 10 g of thecream according to 2.6.

6.4. A cream containing solid lipoid nanoparticles and a medicament wasproduced as follows:

41.2 g of cetostearyl alcohol, 18.5 g of isopropyl myristate and 19.6 gof octamethylcyclotetrasiloxane were heated together at 55° C. 10.3 g ofCETOMACROGOL 1000®, 2.4 g of citric acid (1 aq) and 2.3 g of trisodiumcitrate, were dissolved in 165.6 g of water at 55° C.

Both phases were mixed using a stirrer at 200 R.P.M. The dispersion wascooled under reduced pressure to a temperature of 30° C. To thedispersion of 1.2., 5 g of NIPAGIN B® and 10 g of NIPAGIN P® were added.

146.3 g of the preserved dispersion of 1.2. and 44.2 g of propyleneglycol, in which 0.45 g of hydrocortisone-17α-butyrate was dissolved,were mixed with the cooled dispersion with a stirrer at 220 R.P.M. Theresulting cream was cooled down to ambient temperature at reducedpressure.

6.5. An ointment containing solid lipoid nanoparticles and a medicamentwas produced as follows:

6 g of cetyl dimethicone copolyol, 30 g of isopropyl myristate and 50 gof octamethylcyclotetrasiloxane were heated together at 30° C. To thedispersion of 1.2., 5 g of NIPAGIN B® and 10 g of NIPAGIN P® were added.100 g of the preserved dispersion of 1.2., 1 g of sodium chloride, 2.5 gof citric acid (1 aq) and 2.4 g of trisodium citrate, 0.3 g ofhydrocortisone17α-butyrate and 108.1 g of water were mixed at 30° C.with a magnetic stirrer at 500 R.P.M.

After mixing the aqueous phase was homogenized by sonification. Thehomogenized aqueous phase was added to the above-described oil phasewhilst mixing at 175 R.P.M. using a stirrer. The dispersion was mixed at200 R.P.M. for 1 hour and 300 R.P.M. for 11/2 hour successively. Theresulting cream was cooled to ambient temperature at reduced pressure.

EXAMPLE 7 Production of a Gel, Containing a Suspension of Solid LipoidNanoparticles and a Medicament

7.1. 5 mg of dithranol was hand-mixed in a mortar with 5 g of the gelaccording to 3.3.

7.2. A gel containing solid lipoid nanoparticles and a medicament wasproduced as follows:

To the dispersion of 1.2., 5 g of NIPAGIN B® and 10 g of NIPAGIN P® wereadded. 100 g of the preserved dispersion of 1.2., 6 g of isopropylmyristate, 1.8 g of citric acid (1 aq), 8.2 g of a 10 wt % solution ofsodiumhydroxide and a solution of 0.305 g of hydrocortisone-17α-butyratein 60 g of propylene glycol were mixed together using a stirrer at 150R.P.M. and a TURRAX® homogenizer at 2000 R.P.M. 128.1 g of a 5 wt %aqueous dispersion of CARBOPOL 981® was added whilst stirring at 150R.P.M. at reduced pressure.

EXAMPLE 8 In Vitro Occlusivity Test

The suspensions according to 1.1 and 1.2, and the creams according to2.2., 2.3. and 2.4., were compared in the following in vitro occlusivitytest:

A vessel in the form of a beaker was used. The vessel had a diameter of5.5 cm and a height of 7 cm, and was designed to receive on top aclosing standard laboratory paper filter (TVN, sold by Schut, TheNetherlands), surface 23.8 cm². The test was performed by placing 50 gof distilled water in the vessel, closing the vessel with the paperfilter on the upper surface of which 200 mg of the preparation to betested was evenly distributed, and placing the closed vessel for aperiod of 72 hours in a stove at 33° C. and 58% RH. All other conditionshaving been kept equal, the weight loss of water from the vessel (waterflux) after 72 hours exclusively depending of the occlusivity of thepreparation tested.

The occlusion factor F of the tested preparation was calculatedaccording to the equation:

    F=100((A-B)/A)

wherein A is the water flux through the uncovered filter, and B thewater flux through the filter when covered by the tested preparation.

All preparations were tested in triplicate, the maximal deviationbetween the results of one preparation being 10%. The following Table 1presents the means of the occlusion factors F found.

                  TABLE 1    ______________________________________             Water   Lipid      Solid lipoid             content content    particle size                                        Occlusion    Preparation             %       %          nm      Factor F    ______________________________________    1.1.     65.0    30.0       >2000   5.7    1.2.     65.0    30.0          132  78.5    2.2.     62.5    32.5       --      73.0    2.3.     64.3    30.7       >2000   57.0    2.4.     64.3    30.7          132  87.0    ______________________________________

From these results it has appeared, that solid lipoid microparticles aregreatly inferior to solid lipoid nanoparticles in their occlusiveeffect, and that the addition of solid lipoid microparticles to a creamlowers the cream's occlusivity, while the addition of solid lipoidnanoparticles to a cream raises the cream's occlusivity.

EXAMPLE 9 In Vivo Dithranol Irritarcy Test, on the Rabbit Skin

The creams containing dithranol according to 6.1. and 6.3., and the gelcontaining dithranol according to 7.1., were tested for their irritancyin comparison with the PSORICREME® product, a commercially availablecream of Essex labs, also containing 0.1% of dithranol.

The backs of four rabbits (albino females of the New Zealand Whitebreed) were shaven. On the next day the preparations to be tested wereapplied once, 8 preparations per back, randomized in an a-select manner.In each application 0.05 ml of the preparation was applied to a skinarea of 2×2 cm. 20 and 140 hours after the preparations were applied,the skin irritation was scored by two independent scorers, according toan arbitrary scale running from 0 to 4 (0means no erythema, 4 meanssevere erythema).

Table 2 presents the mean irritancy scores.

                  TABLE 2    ______________________________________                  Skin irritancy                             Score after application    Preparation   at 20 hours                             at 140 hours    ______________________________________    6.1.          1.0        0.5    6.3.          1.7        1.3    7.1.          0.5        0.6    PSORICREME ®                  2.4        3.4    ______________________________________

From these results it has appeared, that the preparations according tothe invention are much less irritating to the skin than a conventionalpreparation containing the same amount of an irritating medicament.

EXAMPLE 10 In Vivo Dithranol Anti-proliferative Activity Test, on theMouse Skin

The creams containing dithranol according to 6.1. and 6.3., and the gelcontaining dithranol according to 7.1., were tested for their activityin comparison with the PSORICREME® product, a commercially availablecream of Essex labs, also containing 0.1% of dithranol.

The reduction of the uptake of thymidine in the DNA of theepidermis wasused as a measure of the anti-proliferative activity of dithranol.

Groups of 10 hairless mice (Hr/hr; Bommice; females) were used. Thetested formulations were applied in a quantity of 25 μl to an area of2×2 cm of their skin, which was compared to 2×2 cm of untreated skin(control). One hour after application the mice received a subcutaneousinjection of 25 μl, containing 25 μCi ³ H-thymidine (Amersham). Threehours after application the mice were killed, their treated anduntreated 2×2 cm skin areas prepared, and their epidermis separated byincubation in 2M potassium bromide. Subsequently, the amount ofradioactive thymidine, taken up in the DNA of the epidermis in twohours, was measured by using a scintillation counter (TRI-CARB®,Packard).

Table 3 presents the means and standard deviations of thymidine uptakein the treated areas, as percentages of the untreated control areas.

                  TABLE 3    ______________________________________                 Thymidine uptake, % of controls    Preparation    Mean      St. deviation    ______________________________________    6.1.           45        14    6.3.           42        15    7.1.           47        18    PSORICREME ®                   39        15    ______________________________________

From these results it has appeared, that the anti-proliferative activityof the tour tested dithranol formulations is of the same order.

EXAMPLE 11 A Combination of a Blanching and Cosmetic Test in Vivo onHumans

Preparations 6.4., 6.5., 7.2. and LOCOID® cream (0.1 wt %hydrocortisone-17α-butyrate; Brocades Pharma B.V., the Netherlands)containing 23, 20, 12 and 28.1 wt % of non-volatile occlusive lipids,respectively, were tested in a McKenzie-Stoughton vaso-constriction testand a cosmetic test.

11.1. McKenzie-Stoughton vasoconstriction test

The in vivo skin blanching effects of the preparations according to6.4., 6.5., 7.2. and LOCOID® cream were compared in a McKenzie-Stoughtonvasoconstriction test.

The test was conducted on a panel of non-patient volunteers (1 femaleand 7 males). Sites were marked on the flexor aspect of both fore-armsby light indentation with a circular punch of 15 mm diameter. Sites wereat least 4 cm distant from wrist and elbow. The precoded preparationswere applied to these sites according to a Latin square experimentaldesign. Preparations were applied by technicians, in amounts of 10 μlper site using a Hamilton injection syringe (Gastight 1710) fitted witha 18 gauge blunt needle. The application sites were then covered, butnot occluded with a guard, which was held in place with a ring ofsurgical tape (diameter: external 50/60 mm, internal 25 mm). Dressingswere removed and arms were washed with soap and luke-warm water 17 hoursafter application of the formulations. Accordingly, blanching at thevarious sites was assessed by determining the change in the luminescenceparameter L* of the treated skin as compared to the untreated skin(L*₀), using a MINOLTA CHROMAMETER C300®. This was done at 1, 3 and 6hours after removal of the preparations. The experiment was conducted ina double blind fashion.

The results of this study (see FIG. 1) showed that there was nostatistical significant difference between the four preparations tested.

11.2. Cosmetic acceptability test

For performing the cosmetic acceptability test preparations wereprepared in accordance with 6.4., 6.5. and 7.2. but without addinghydrocortisone-17α-butyrate. As references LOCOID® cream base (withouthydrocortisone-17α-butyrate) and the highly appreciated cosmeticnon-ionic liposomal cream CANDERMYL® (Alcon, Galderma, France) wereused. All preparations were coloured with a small amount of the yellowcolorant E102 and were perfumed with a small amount of a lavenderfragrance.

The preparations were compared in 20 non-patient volunteers in aleft-right cosmetic acceptability study. Every volunteer participatedthree times in a double blind manner. 50 μl of the precoded preparationswere applied on the flexor aspect of both forearms by a technician. Thevolunteer had to answer questions about the appearance, spreadingproperties, stickiness, skin-feel of the preparations and finally thevolunteer was asked to rank the preparations with respect to his/herpreference. In total 60 preferences were given. The results arepresented in Table 4.

                  TABLE 4    ______________________________________    Preparation     Number of preferences    ______________________________________    6.4.            14    6.5.            16    7.2.            15    LOCOID ® cream base                     7    CANDERMYL ® cream                     8    ______________________________________

From the results presented in Table 4, it has appeared that the threesolid lipoid nanoparticles containing preparations are cosmeticallysuperior over the two reference preparations.

Considering the results of both the McKenzie-Stoughton vasoconstrictiontest and the cosmetic acceptability test it has appeared that theeffectiveness of the medicament remains the same whilst the appreciationof the cosmetic properties is increased when non-volatile occlusivelipids in a topical formulation are replaced by a suspension of solidlipoid nanoparticles, according to the invention.

EXAMPLE 12 In Vitro Nail Penetration Using Lotions, Containing SolidLipoid Nanoparticles and Oxiconazole Nitrate, and Lotions ContainingN-acetylcysteine and Oxiconazole

The lotion of 4.2. and as a reference a clear solution containing 1.5 gof N-acetylcysteine, 0.115 g of oxiconazole nitrate, 0.02 g of a limefragrance and 0.0375 g of hydroxypropylcellulose in a vehicle consistingof 0.2 g of benzyl alcohol, 0.33 g of water and 6.52 g of ethanol, weretested for the ability of oxiconazole to penetrate into a pig's nail. Toboth preparations 1 μCi ¹⁴ C-oxiconazole per 30 μl preparation wasadded.

From a pig's nail 8 mm discs were punched. Two times a day (for 7 days)2 μl of the preparations were applied after cleaning twice theapplication area with 15 μl of demineralized water and 15 μl ofdehydrated alcohol. After 7 days of application 3 mm discs were punchedfrom the application area, the discs were sliced into slices of 50 μm.

The amount of labelled oxiconazole in the slices was determined using ascintillation counter. The determined amount of labelled oxiconazole wasused to calculate the total amount of oxiconazole within the slice.

The amount of oxiconazole per slice and the total amount of oxiconazolepenetrated are graphically represented in FIG. 2 and 3, respectively.

From FIGS. 2 and 3 it has appeared that the solid lipoid nanoparticlescontaining preparation causes an increase of the oxiconazoleconcentration per nail slice and per whole nail, respectively, withrespect to the preparation containing N-acetylcysteine and oxiconazolenitrate.

I claim:
 1. A preparation for topical application to a human bodycomprising an aqueous suspension of solid lipoid nanoparticles in aconcentration of between 0.01 and 60 wt %,said nanoparticles comprisingat least one solid paraffin lipid and optionally at least one emulsifierand having a mean particle size of 100 to 400 nm and said suspensionfurther containing a topically effective amount of a mcdicament externalto said particles, wherein the medicament is selected from the groupconsisting of steroidal anti-inflammatory compounds, anti-mycotics,anti-psoriatics, anti-eczema agents, anti-proliferatives and dithranol.2. The preparation of claim 1 wherein said concentration is 5 to 45 wt.%, based on the suspension.
 3. The preparation of claim 1 wherein thelipid is a hard paraffin, having a melting point of 54-57° C.
 4. Amethod for the production of a preparation for topical application to ahuman body, said preparation comprising an aqueous suspension of solidlipoid nanoparticles in a concentration of between 0.01 and 60 wt %,said nanoparticlcs comprising at least one solid paraffin lipid andoptionally at least one emulsifier and having a mean particle size of100 to 400 nm, said suspension containing a topically effective amountof a medicament external to the nanoparticles, wherein the medicament isselected from the group consisting of steroidal anti-inflammatorycompounds, anti-mycotics, anti-psoriatics, anti-eczema agents,anti-proliferatives and dithranol, said method comprising:a) melting asolid lipid or a mixture of solid lipids in a heated aqueous liquid,optionally in the presence of an effective amount of said emulsifier toprovide emulsification whereby molten lipid is formed; b) vigorouslydispersing the molten lipid in the aqueous liquid, whereby a dispersionof molten lipoid droplets of 100 to 400 nm is formed and c) allowingsaid dispersion to cool until said lipoid droplets solidify and asuspension of said solid lipoid nanoparticles is formed.
 5. A method ofmedical or cosmetic treatment of a human body, comprising the topicalapplication of a preparation comprising an aqueous suspension of solidlipoid nanoparticles in a concentration of between 0.01 and 60 wt %,said nanoparticles comprising at least one solid paraffin lipid andoptionally at least one emulsifier, and having a mean particle size ofbetween 100 and 400 nm, and said suspension containing a topicallyeffective amount of a medicament, selected from the group consisting ofsteroidal anti-inflammatorv compounds, anti-mycotics, anti-psoriatics.anti-eczema agents, anti-proliferatives and dithranol, external to thenanoparticles.